1. Field of the Invention
The invention relates generally to substituted 2-aminotetralins useful in treating schizophrenic disorders in humans.
2. Background of the Art
Schizophrenic disorders are mental disorders with a tendency toward chronicity which impairs functioning and which is characterized by psychotic symptoms involving disturbances of thinking, feeling and behavior. Some of the criteria for the diagnosis of a schizophrenic disorder are delusions, hallucinations, formal thought disorder and a deterioration from a previous level of functioning. Schizophrenia specifically excludes organic mental disorders or mental retardation.
Schizophrenia has a worldwide distribution and a lifetime prevelance of 0.2 to 1% as found in studies of Asian and European populations. Higher rates are found in the U.S.A. and U.S.S.R, although the criteria used in these countries are often much broader. Schizophrenia becomes manifest in late adolescence or early adult life. Even with available forms of treatment, schizophrenic patients are said to occupy about half the hospital beds of the mentally ill and mentally retarded patients; and about 1/4 of all available hospital beds. Schizophrenia has been found to be found highly prevalent in lower socioeconomical classes which may be attributed to social disorganization and the resulting stresses; but, also there is evidence that this association arises partly because some patients, in a prepsychotic phase, drift down the social scale.
Although schizophrenia is thought to be caused by a complex of both inherited and environmental factors, approximately 10% of the relatives of schizophrenics will be recognized as schizophrenic. Thus, a genetic predisposition is probably necessary, if schizophrenia is to occur at all. The main treatments for schizophrenia are chemotherapeutic, in combination with the development of a therapeutic relationship with a skilled counselor, social support, rehabilitation and retraining. Accepted treatments for schizophrenia include the administration of neuroleptics such as haloperidol, chlorpromazine or thioridazine delivered parenterally or orally. The most widely accepted theory of the mode of action of these compounds is that they block dopamine receptor sites in the CNS (Seeman, Pharmacol. Rev. 32 229313, 1980) Other drugs of choice for the biochemical therapy of schizophrenia include butyrophenones, thioxanthenes, dihydroindolones and dibenzoxazepines.
Recently, many patents have issued disclosing the use of different chemical entities for treatment of schizophrenia. For example, in U.S. Pat. No. 4,577,020 certain aminoalkyl and aminoalkenyl triazoles are disclosed as useful antipsychotic drugs. In U.S. Pat. No. 4,588,721 a process for preventing the negative symptoms of schizophrenia is disclosed, which utilizes, as the active agent, a class of compounds which may be defined as benzodiazepines. U.S. Pat. No. 4,593,041 utilizes benzopyrone-type drugs for the treatment of schizophrenia. U.S. Pat. No. 4,626,549 suggests that certain 3-aryloxy-3-phenylpropyl-amines may be used in the treatment of schizophrenia. Finally, U.S. Pat. No. 4,620,977 discloses that certain N,N-dimethylated indolamines, are useful for the treatment of schizophrenia.
While there are many theories as to the neurochemical nature of the illness, it is thought by some researchers that schizophrenia results from a hyperactivity of dopamine-containing neurons in certain areas of the brain. Recently it has been suggested that a new approach to the treatment of schizophrenia could possibly be achieved by selectively stimulating dopamine autoreceptors (which control dopamine synthesis and release and are of the D.sub.2 type) rather than blocking postsynaptic dopamine receptors with the classical neuroleptics (Meltzer, Schiz. Bulln., 6 456-475, 1980). It has also been reasoned that this could lead to fewer CNS-related side effects.
In the case of two dopamine agonists, i.e. apomorphine and N-propylnorapomorphine, clinical studies have tended to support the above proposal (Tamminga et al., Science, 200 567-568, 1978, Tamminga et al., Arch. Gen. Psy. 43, 398-402. Thus, there is this extensive interest in discovering new dopamine agonists which have a selective action on dopamine autoreceptors. See also J. C. Van Oene et al, European Journal of Pharmacology, 87 (1983), pgs. 491-495 and J. C. Van Oene et al, European Journal of Pharmacology, 102 (1984), pgs. 101-115 and Annual Reports in Medicinal Chemistry--20, Chapter 5, entitled "Dopamine Receptors and Dopaminergic Agents" by Schaus et al.
Thus, it is clear from the above that the search for chemical agents or drugs useful for the treatment of schizophrenia is continuing.